A5088564413- CRISPR and Genetic Engineering
- Single-cell and spatial transcriptomics
- Neuroinflammation and Neurodegeneration Mechanisms
- Advanced biosensing and bioanalysis techniques
- RNA Research and Splicing
- RNA and protein synthesis mechanisms
- Genetic Associations and Epidemiology
- Genomics and Chromatin Dynamics
- T-cell and B-cell Immunology
- Cell Image Analysis Techniques
- Epigenetics and DNA Methylation
- Gene expression and cancer classification
- Alzheimer's disease research and treatments
- Cancer Genomics and Diagnostics
- Inflammation biomarkers and pathways
- Immune Cell Function and Interaction
- DNA Repair Mechanisms
- interferon and immune responses
- Bioinformatics and Genomic Networks
- RNA regulation and disease
- Genetic Mapping and Diversity in Plants and Animals
- Systemic Lupus Erythematosus Research
- Radiomics and Machine Learning in Medical Imaging
- Gene Regulatory Network Analysis
- Cancer Cells and Metastasis
Whitehead Institute for Biomedical Research
2019-2025
University of California, San Francisco
2016-2025
Massachusetts Institute of Technology
2019-2025
Massachusetts General Hospital
2016-2025
Howard Hughes Medical Institute
2016-2023
Universidad Católica de Santa Fe
2022
University of San Francisco
2021
QB3
2016-2019
Broad Institute
2013-2017
Brigham and Women's Hospital
2013-2017
We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects established a reference map the architecture MS that includes 200 autosomal susceptibility variants outside major histocompatibility complex (MHC), one chromosome X variant, 32 within extended MHC. used an ensemble methods to prioritize 551 putative genes implicate innate adaptive pathways distributed across cellular components immune system. Using expression profiles from purified human microglia, we...
To extend our understanding of the genetic basis human immune function and dysfunction, we performed an expression quantitative trait locus (eQTL) study purified CD4(+) T cells monocytes, representing adaptive innate immunity, in a multi-ethnic cohort 461 healthy individuals. Context-specific cis- trans-eQTLs were identified, cross-population mapping allowed, some cases, putative functional assignment candidate causal regulatory variants for disease-associated loci. We note...
The prokaryotic CRISPR (clustered regularly interspaced palindromic repeats)-associated protein, Cas9, has been widely adopted as a tool for editing, imaging, and regulating eukaryotic genomes. However, our understanding of how to select single-guide RNAs (sgRNAs) that mediate efficient Cas9 activity is incomplete, we lack insight into chromatin impacts targeting. To address this gap, analyzed large-scale genetic screens performed in human cell lines using either nuclease-active or...
A central goal of genetics is to define the relationships between genotypes and phenotypes. High-content phenotypic screens such as Perturb-seq (CRISPR-based with single-cell RNA-sequencing readouts) enable massively parallel functional genomic mapping but, date, have been used at limited scales. Here, we perform genome-scale targeting all expressed genes CRISPR interference (CRISPRi) across >2.5 million human cells. We use transcriptional phenotypes predict function poorly characterized...
Single-cell (sc)RNA-seq, together with RNA velocity and metabolic labeling, reveals cellular states transitions at unprecedented resolution. Fully exploiting these data, however, requires kinetic models capable of unveiling governing regulatory functions. Here, we introduce an analytical framework dynamo (https://github.com/aristoteleo/dynamo-release), which infers absolute velocity, reconstructs continuous vector fields that predict cell fates, employs differential geometry to extract...
Tumor evolution is driven by the progressive acquisition of genetic and epigenetic alterations that enable uncontrolled growth expansion to neighboring distal tissues. The study phylogenetic relationships between cancer cells provides key insights into these processes. Here, we introduced an evolving lineage-tracing system with a single-cell RNA-seq readout mouse model Kras;Trp53(KP)-driven lung adenocarcinoma tracked tumor from single-transformed metastatic tumors at unprecedented...
Manifold destiny Mapping of genetic interactions (GIs) is usually based on cell fitness as the phenotypic readout, which obscures mechanistic origin interactions. Norman et al. developed a framework for mapping and understanding GIs. This approach leverages high-dimensional single-cell RNA sequencing data gathered from CRISPR-mediated, pooled perturbation screens. Diverse transcriptomic phenotypes construct “manifold” representing all possible states cell. Each GI projects state to...
Current single-cell RNA-sequencing approaches have limitations that stem from the microfluidic devices or fluid handling steps required for sample processing. We develop a method does not require specialized devices, expertise hardware. Our approach is based on particle-templated emulsification, which allows encapsulation and barcoding of cDNA in uniform droplet emulsions with only vortexer. Particle-templated instant partition sequencing (PIP-seq) accommodates wide range emulsification...
In the mitochondrial outer membrane, α-helical transmembrane proteins play critical roles in cytoplasmic-mitochondrial communication. Using genome-wide CRISPR screens, we identified carrier homolog 2 (MTCH2), and its paralog MTCH1, showed that it is required for insertion of biophysically diverse tail-anchored (TA), signal-anchored, multipass proteins, but not membrane β-barrel proteins. Purified MTCH2 was sufficient to mediate into reconstituted proteoliposomes. Functional mutational...
A microglial-like cellular model can be used to identify functional consequences of genetic variants associated with neurodegenerative disease.
FOXP3(+) regulatory T (Treg) cells enforce immune self-tolerance and homeostasis, variation in some aspects of Treg function may contribute to human autoimmune diseases. Here, we analyzed population-level variability by performing genome-wide expression profiling CD4(+) conventional (Tconv) from 168 donors, healthy or with established type-1 diabetes (T1D) type-2 (T2D), relation genetic immunologic screening. There was a range signature transcripts, almost invariant, others more variable,...
CRISPR interference (CRISPRi) enables programmable, reversible, and titratable repression of gene expression (knockdown) in mammalian cells. Initial CRISPRi-mediated genetic screens have showcased the potential to address basic questions cell biology, genetics, biotechnology, but wider deployment CRISPRi screening has been constrained by large size single guide RNA (sgRNA) libraries challenges generating models with consistent knockdown. Here, we present next-generation sgRNA effector...
Genome-wide association studies have linked variants in TREM2 (triggering receptor expressed on myeloid cells 2) and TREML2 with Alzheimer disease (AD) AD endophenotypes. Here, we pursue a targeted analysis of the TREM locus relation to cognitive decline pathological features AD.Clinical, cognitive, neuropathological phenotypes were collected 3 prospective cohorts aging (n = 3,421 subjects). Our primary was an neuritic plaque pathology. To functionally characterize associated variants, used...
Genomic and proteomic screens have identified numerous host factors of SARS-CoV-2, but efficient delineation their molecular roles during infection remains a challenge. Here we use Perturb-seq, combining genetic perturbations with single-cell readout, to investigate how inactivation changes the course SARS-CoV-2 response in human lung epithelial cells. Our high-dimensional data resolve complex phenotypes such as shifts stages modulations interferon response. However, only small percentage...
A proportion of multiple sclerosis (MS) patients experience disease activity despite treatment. The early identification the most effective drug is critical to impact long-term outcome and move toward a personalized approach. aim present study identify biomarkers for further clinical development yield insights into pathophysiology activity.We performed genome-wide association in interferon-β (IFNβ)-treated MS followed by validation 3 independent cohorts. role validated variant was examined...